Abstract
Enterovirus 71 (EV71) causes seasonal epidemics of hand-foot-and-mouth disease and has a high mortality rate among young children. We recently demonstrated potent induction of the humoral and cell-mediated immune response in monkeys immunized with EV71 virus-like particles (VLPs), with a morphology resembling that of infectious EV71 virions but not containing a viral genome, which could potentially be safe as a vaccine for EV71. To elucidate the mechanisms through which EV71 VLPs induce cell-mediated immunity, we studied the immunomodulatory effects of EV71 VLPs on human monocyte-derived dendritic cells (DCs), which bind to and incorporate EV71 VLPs. DC treatment with EV71 VLPs enhanced the expression of CD80, CD86, CD83, CD40, CD54, and HLA-DR on the cell surface; increased the production of interleukin (IL)-12 p40, IL-12 p70, and IL-10 by DCs; and suppressed the capacity of DCs for endocytosis. Treatment with EV71 VLPs also enhanced the ability of DCs to stimulate naïve T cells and induced secretion of interferon (IFN)-γ by T cells and Th1 cell responses. Neutralization with antibodies against Toll-like receptor (TLR) 4 suppressed the capacity of EV71 VLPs to induce the production of IL-12 p40, IL-12 p70, and IL-10 by DCs and inhibited EV71 VLPs binding to DCs. Our study findings clarified the important role for TLR4 signaling in DCs in response to EV71 VLPs and showed that EV71 VLPs induced inhibitor of kappaB alpha (IκBα) degradation and nuclear factor of kappaB (NF-κB) activation.
Highlights
Enterovirus 71 (EV71) is responsible for seasonal epidemics of hand-foot-and-mouth disease and is associated with a high mortality rate [1], aseptic meningitis, and severe neurological complications [2] in young children
Human dendritic cells (DCs) were incubated with EV71 virus-like particles (VLPs) for 30 min on ice to allow binding to the cell surface
We found that EV71 VLPs could bind to DCs in a concentration-dependent manner (Figure 1A and B)
Summary
Enterovirus 71 (EV71) is responsible for seasonal epidemics of hand-foot-and-mouth disease and is associated with a high mortality rate [1], aseptic meningitis, and severe neurological complications [2] in young children. No antiviral drugs or vaccines effective against EV71 are available, and measures to prevent EV71 epidemics rely exclusively on public surveillance. Immunization with inactivated intact EV71 virus (10 mg/mouse) induces immune responses and confers protection against lethal EV71 infection in mouse models [4]. Vaccines based on recombinant DNA technology promise to mitigate these risks. DNA vaccines (100 mg/mouse) and recombinant protein vaccines (10 mg/mouse) based on VP1, the most potent antigen (Ag) on the EV71 virus, induce poorer immune responses than inactivated virus vaccines and fail to effectively protect mice against infection by EV71 [4]
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